Total synthesis ad biological evaluation of JBIR-23

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Human malignant pleural mesothelioma (MPM) is an aggressive (fatal) lung cancer which is always associated with asbestos exposure. Typically symptoms do not appear until 20-40 years after the original exposure, with life expectancy then 12-18 months. Given the widespread use of asbestos during the 20th century and this long latency period, it is no surprise that cases of MPM continue to rise. Therefore there is an urgent need to develop novel therapeutic approaches for the treatemnt of MPM.Thus the development of new therapeutic agents is crucial. Almost all drugs on the market - for any symptom - tend to have their origins in a natural product: that is something isolated from nature. Unfortunately there are no novel drugs in development specifically targeting mesothelioma. The principle reason for this was that until recently, there were no reported natural products to serve as a lead compound - a starting point for the drug discovery process.This changed in 2009, with the report of JBIR-23 and -24, two microbial metabolites isolated from Streptomyces sp. AK-AB27: the first natural products specifically to demonstrate cytotoxicity against four MPM cell lines, with modest IC50 values of 10-50 uM.The overall aim of the project s to investigate the first synthesis of JBIR-23; to confirm its structure is the one proposed upon its isolation; to prepare a library of analogues of JBIR-23; finally to conduct extensive biological studies on these compounds.